1-23795992-C-T

Position:

• chr1-23795992-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_001008216.2(GALE):​c.1004G>A​(p.Arg335His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.83

Genes affected

GALE (HGNC:4116): (UDP-galactose-4-epimerase) This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GALE (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_001008216.2 (GALE) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 1-23795992-C-T is Pathogenic according to our data. Variant chr1-23795992-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2503917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALE	NM_001008216.2	c.1004G>A	p.Arg335His	missense_variant	12/12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4	c.1004G>A	p.Arg335His	missense_variant	12/12		NP_000394.2
GALE	NM_001127621.2	c.1004G>A	p.Arg335His	missense_variant	11/11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5	c.1004G>A	p.Arg335His	missense_variant	12/12	1	NM_001008216.2	ENSP00000483375.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250928 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

UDPglucose-4-epimerase deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2023	Variant summary: GALE c.1004G>A (p.Arg335His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250928 control chromosomes. c.1004G>A has been reported in the literature in at least two compound heterozygous newborns with severely reduced enzyme activity in red blood cells, but without obvious clinical symptoms, suggesting that they had the benign- or peripheral form of UDPglucose-4-Epimerase Deficiency (Park_2005), and in at least another individual with epimerase-deficiency galactosemia, however no phenotype details were provided (Henderson_2001). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a moderate decrease in UDP-galactose epimerization activity, ranging from ~40 to 70% of the wild-type (Timson_2005, Bang_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19250319, 16302980, 16301867, 11903335). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified for the peripheral form of the disease as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects GALE function (PMID: 16302980, 19250319). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GALE protein function. ClinVar contains an entry for this variant (Variation ID: 2503917). This missense change has been observed in individual(s) with galactosemia (PMID: 16301867). This variant is present in population databases (rs368637540, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 335 of the GALE protein (p.Arg335His). -

GALE-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2023

The GALE c.1004G>A variant is predicted to result in the amino acid substitution p.Arg335His. This variant has been reported in the compound heterozygous state in two individuals with galactosaemia epimerase deficiency (Park et al 2005. PubMed ID: 16301867; 2005. PubMed ID: 16302980). Arg335 is located on α-helix 10 on the protein surface (McCorvie et al. 2013. PubMed ID: 23644136). Functional studies showed that this variant causes mild defects in enzyme activity (Timson et al. 2005. PubMed ID: 16302980; Bang YL et al 2009. PubMed ID: 19250319). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24122482-C-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;D;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.055	.;T;T
Sift4G	Benign	0.073	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.68
MVP		0.93
MPC		0.65
ClinPred		0.87	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368637540; hg19: chr1-24122482;